# Pathogenesis of Emery-Dreifuss Muscular Dystrophy

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $341,929

## Abstract

PROJECT SUMMARY
Emery-Dreifuss muscular dystrophy (EDMD) is a genetically heterogenous syndrome that results from
mutations in genes encoding nuclear envelope proteins. It is characterized by scapulohumeral-peroneal
myopathy, early joint contractures and a lethal dilated cardiomyopathy with conduction defects. Mutations in
EMD, which encodes an integral protein of the inner nuclear membrane called emerin, cause X-linked EDMD.
Mutations in LMNA, which encodes A-type lamins, cause autosomal EDMD. Lamins are intermediate filament
proteins lining the inner nuclear membrane. Extremely rare cases of EDMD-like disorders have been linked to
mutations in genes encoding other nuclear envelope proteins, including TOR1AIP1 that encodes lamina-
associated polypeptide 1 (LAP1), an integral protein of the inner nuclear membrane. Emerin, A-type lamins
and LAP1 all interact with each other and indirectly with muscle cytoskeletal structural proteins. Our research
during previous cycles of this continuing project has provided new insights into the pathobiology of EDMD.
However, there are still challenges to deciphering the pathogenic mechanisms underlying the heart and
skeletal muscle pathology in EDMD and in translating fundamental discoveries towards the treatment of
patients. One is the lack of small animal or adequate cellular models of X-linked EDMD caused by emerin
deficiency. Another is developing approaches to determine if skeletal muscle pathology occurs primarily as a
result of defects in differentiated myofiber structural integrity, in regeneration of damaged fibers or both. This
proposal addresses these challenges. Our first hypothesis is that similar pathogenic cell signaling and gene
expression abnormalities are responsible for dilated cardiomyopathy in both X-linked and autosomal EDMD.
Our second hypothesis is that alterations in EDMD-associated proteins affect both the structural integrity of
differentiated skeletal muscle fibers and the ability of injured muscle to regenerate. Specific Aim 1 will address
the first of these hypotheses. We will generate a mouse model of cardiomyopathy in X-linked EDMD as well as
isogenic cultured cardiomyocytes with EMD, LMNA and TOR1AIP1 mutations. This will allow us to determine if
the same cell signaling and gene alterations occur in the heart in X-linked and autosomal EDMD. Specific Aim
2 will investigate the effects of EDMD-causing gene mutations on differentiated skeletal muscle. To do so, we
will generate mice in which the encoded proteins can be depleted from differentiated adult myofibers and
examine the pathological, physiological and gene expression abnormalities that occur. Specific Aim 3 will
examine the role of EDMD-associated proteins in skeletal muscle regeneration. This will be accomplished by
depleting the proteins specifically from skeletal muscle satellite cells and assessing regeneration after injury.
Successful completion of these Aims will advance our understanding of the cardiac and skeletal m...

## Key facts

- **NIH application ID:** 10212239
- **Project number:** 5R01AR048997-17
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Howard J Worman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $341,929
- **Award type:** 5
- **Project period:** 2003-05-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212239

## Citation

> US National Institutes of Health, RePORTER application 10212239, Pathogenesis of Emery-Dreifuss Muscular Dystrophy (5R01AR048997-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10212239. Licensed CC0.

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